Plasma HDL cholesterol and apoA-I are epidemiologically associated with risk of premature coronary heart disease, but are not always predictive in individual patients. One example are the genetic syndromes of LCAT deficiency. LCAT is a plasma enzyme which catalyzes the formation of HDL cholesteryl ester in plasma. Patients with classic (complete) LCAT deficiency and with a partial LCAT deficiency termed fish-eye disease (FED) have very low levels of HDL and apoA-I but do not have an increased risk of premature CHD. We investigated HDL apoA-I and apoA-II in a total of five patients with different types of LCAT deficiency using both endogenous labeling with stable isotopes and exogenously labeled radiotracers. We found that apoA-I and especially apoA-II were catabolized substantially faster than in control subjects, accounting for their low levels in plasma. The two major classes of HDL particles include those containing only apoA-I (LpA-I) and those containing both apoA-I and apoA-II (LpA-I:A-II). LpA-I, but not LpA-I:A-II, has been found to be specifically associated with risk of premature CHD. We have previously established that in normal subjects the catabolism of apoA-I on LpA-I is significantly faster than that of apoA-I on LpA-I:A-II, indicating that the metabolic regulation of these two HDL particles is fundamentally divergent. In the LCAT deficient patients, however, the catabolism of LpA-I:A-II was markedly faster than that of LpA-I, resulting in plasma levels of LpA-I:A-II that were proportionately much lower than those of LpA-I. This could be an explanation for the observation that these patients are not at increased risk for premature CHD despite their low levels of HDL. We have also investigated HDL metabolism in a series of five other patients who also have very low levels of HDL but no CHD. In these patients we also found rapid catabolism of apoA-I, apoA-II, and LpA-I:A-II accounting for the low plasma levels of these apolipoproteins. These studies demonstrate that not all syndromes of low HDL necessarily predispose to premature CHD, and that rapid catabolism of LpA-I:A-II may be one cause of low HDL not associated with increased risk of CHD.